David R. Byrd, MD Chair, AJCC

1. Changes to Breast Cancer Staging, AJCC 8th Ed Cancer Staging Manual/Challenges in Staging after Neoadjuvant Systemic Treatment David R. Byrd, MD Chair, AJCC Surgical Oncology, University of Washington/Seattle Cancer Care Alliance Seattle, WA

2. Disclosures • I have no financial disclosures relevant to this presentation • Member of the AJCC 8th Ed Cancer Staging Manual editorial board • Chair, AJCC • I have a strong bias, FAVORING tumor registrars and their dedication.

3. Staging – The Foundation of Cancer Care • Understanding the extent of cancer, its prognosis, and impact of therapy are central to personalized care; and to improving cancer impact on society • Staging is the common language of cancer care • Clinical care • Define extent and prognosis of cancer • Guide appropriate treatment • Basis for Guidelines • NCCN Guidelines all base recommendations on cancer stage • Communicate among users about groups of patients • Population impact of cancer; Changes over time • Group similar cases for clinical trials

4. Periodic Updating of the AJCC / TNM Staging

5. Key Elements and Terminology of Staging • STAGE: The aggregate information resulting from T, N, M • Anatomic groups – Anatomy only • Prognostic stage groups – Anatomy PLUS key non-anatomic factors • Categories: The individual information on • T • N • M • There is no such thing as “T-Stage” or “N-Stage” – they are categories

6. T, N, M categories: Breast Cancer Example

7. Stage: Groups Based on T, N, M • Stage Groups defined by combinations of T, N and M for patients with generally similar prognosis • Prognostic Stage Groups defined by similar groups of T, N, M + selected non-anatomic factors • In general: • Stage 0 non-invasive cancer • Stage I Small cancers; node negative • Stage II Larger/more extensive plus/minus positive nodes • Stage III Larger/extensive; increasing extent of positive nodes • Stage IV Cancers with distant metastases

8. Staging Classifications – Time Points of Staging • Clinical • Before initiation of treatment: prefix ”c” –cT, cN • All information from history, physical examination and imaging • Whatever is available – advanced imaging NOT required • Pathological • Clinical information • PLUS results of surgery (if surgery initial treatment): prefix pT, pN • Post-therapy (post-neoadjuvant) • Clinical or pathologic information after completion of systemic or radiation therapy if this treatment precedes / replaces surgery: prefix ycT; ycN, prefix ypT; ypN if surgery then performed • Less Commonly Used: • Recurrent – Extent of disease at recurrence: prefix rT, rN • Autopsy – For cancer identified only at autopsy

9. Understanding Stage Classifications Pathological – p* Surgical Treatment Clinical - c Pathology Report Diagnostic Workup –Hx and Phys exam, imaging, bx Date of Diagnosis Surgical Treatment Systemic or Radiation Therapy Evaluation by imaging & physical exam Pathology Report Clinical - c Posttherapy - yc Posttherapy - yp • Includes post-surgery imaging if within 4 months of Dx; • in the absence of disease progression or systemic Rx or RT

10. Key Important Rule in Assigning Stage:The Role of the Managing Physician • Staging requires collaborative effort for information from many professionals • Assigning stage requires synthesis of information from an array of many sources • History and Physical • Imaging; Pathology; Biopsy and diagnostic procedures • Surgical findings (beyond pathology report - e.g. status of other organs; invasion of local structures) • Managing Physician (NOT pathologist / radiologist) assigns the final cancer stage • Pathologist and radiologist provide important information to help assign stage related to T-, N-, and M- categories from the data they have available • BUT it is the managing physician who must synthesize all this information and make the final assignment of the clinical, pathological and post-therapy stage.

11. Anatomic Stage is Key Predictor of Breast Cancer Outcome: The National Cancer Data Base 10‐year survey of breast carcinoma treatment at hospitals in the US Cancer; Volume 83, Issue 6, pages 1262-1273

12. Staging Needs to Be Relevant to Practice • Anatomic staging valuable but not always sufficient • Many cancer types do not have validated non-anatomic factors to modify anatomic state • Advanced cancer characterization and biomarker determination not available in many parts of the world • Providers use other information • Biomarkers / subtypes • Genomic profiling • Specific molecular targets • “Staging” must incorporate new information beyond anatomy to remain relevant and useful

13. Evolution of Anatomic to AJCC “Prognostic” Staging • Non-anatomic factors in AJCC TNM since inception • Soft tissue sarcoma – grade included in 1st Edition AJCC Manual • Bone – grade including in 2nd Edition AJCC Manual • Thyroid – Age and histologic type included in 2nd Edition Manual • Beginning in the 6th and 7th Editions of AJCC Staging, marked increase in use of non-anatomic factors incorporated to defining Stage Groups • Non-anatomic factors used primarily to modify anatomic stage • Maintain ability to derive pure anatomic stage • Comparisons over time • Allow use of stage around the world as the common language of cancer – even where it is not possible to obtain non-anatomic information

14. AJCC Vision – Evolution to Prognostic Staging The Transition from Population Based to a more “Personalized” Approach Cancer Stage Comprehensive Cancer Profile Population Survival Outcomes Personalized SurvivalOutcomes

15. The 8th EditionPublished Late 2016Breast Updated November 2017Effective for Cases Dx’d 1/1/2018

16. American Joint Committee on Cancer (AJCC) 8th ed. Editorial Board Strategy • Maintain anatomic extent of disease - TNM foundation • Incorporate evidence-based non-anatomic factors, including molecular markers • Era of precision medicine  evolution from a “population based” to a “more personalized” approach • “One size fits all” model does not exist TNM - Anatomic Extent of Disease Evaluate site-specific prognostic & predictive factors Link to “AJCC Approved” Predictive/prognostic risk calculating tools Adapted from Mahul Amin AJCC Cancer Staging Manual. 8th Ed. New York: Springer; 2017

17. 8th Edition Editorial Organization & Structure AJCC Executive Committee Editor-in-Chief CORES DISEASE SITE TEAMS Editorial Board Administrative Core Melanoma Expert Panel Breast Expert Panel Etc…18/19total Expert Panels Evidence Based Medicine & Statistics Core Content Review Cores provide content review specific to their areas of expertise and sign-off prior to final submission. Expert Panel Chair Precision Medicine Core Expert Panel Vice Chair Content Harmonization Core Disease Team Lead(s) Data Collection Core Disease Team(s) Professional Organization & Corporate Relations Core

18. Limitations of Anatomic Staging • Anatomic stage alone does not meet the needs of patients • Rapid evolution in understanding cancer biology has made other factors beyond anatomy as or MORE important in defining prognosis; and in defining optimal therapy

19. Cox regression 10-year breast cancer specific survival estimates by pathologic stage and ER status

20. Breast Cancer Molecular Subtypes are Central to Prognosis and Treatment: Current usage based primarily on ER, PR, HER2 expression

21. Breast Cancer Survival by Subtype Knutsvik G, Stefansson IM, Aziz S, Arnes J, Eide J, Collett K, Akslen LA - PLoS ONE (2014)

22. Treatment Also Defined by Biomarkers:Impact of Trastuzumab in HER2(+) Breast Cancer Perez EA et al. J ClinOncol 2014;32(33):3744

23. Anatomic Stage Insufficient for Treatment Decisions

24. Major Changes in Breast Cancer Staging with 8th Edition • Lobular carcinoma in situ (LCIS) no longer included in AJCC Staging • LCIS is a “benign” entity and not cancer • Should not be in a cancer staging system • Issue with “pleomorphic” LCIS – but insufficient data available • Prognostic Staging – Incorporation of Grade, HER2, ER, PR • Incorporation of genomic profiling to assign pathological prognostic stage group

25. Evolution to Prognostic Staging: Breast Cancer • The AJCC 8th Edition Breast Staging incorporates key prognostic factors into the primary staging • Anatomic stage groups still maintained • Clinical Stage • When biomarkers not available. • “Prognostic Stage” will the the primary stage recorded in cancer registries in the United States • Requires: • T; N; M • Grade; HER2; Estrogen Receptor; Progesterone Receptor • Genomic profiles (OncotypeDx™) as appropriate

26. Evolution to Prognostic Staging: Breast Cancer • The AJCC 8th Edition Breast Staging incorporates key prognostic factors into the primary staging • Anatomic stage groups still maintained for use in areas of world where biomarkers are not available. • “Prognostic Stage” will the the primary stage recorded in cancer registries in the United States • Decision made on 2 separate studies • E Mittendorf– Using MDACC dat • DJ Winchester – Using NCDB • Final changes based on NCDB analysis • Requires: • T; N; M • Grade; HER2; Estrogen Receptor; Progesterone Receptor

27. NCDB Analysis: Survival Range for Assignment to Prognostic Stage Group • NCDB Analysis of cases Dx 2010-2012 • Complete biomarker data • Survival ranges defined for each stage group • Group assigned based on survival; not anatomy

29. Survival Outcomes by Stage Group • Prognostic Stage Groups show better survival differentiation • Include cancers of different anatomic extent but similar biological potential Winchester DJ et al

30. Stage Reassignments with Prognostic Staging • Addition of key biomarkers changes stage groups compared to anatomic staging. • Clinical: 36% reassigned • 20% downstaged • 16% upstaged • Pathological – 39% reassigned Winchester DJ et al

31. Genomic Profiles: Inclusion Based on Level I Evidence • Breast panel included low risk findings on genomic profiles with Level I Evidence • Classify appropriate cases as Stage IA • As of time of printing (early August 2016) only 21 Gene Recurrence Score (OncotypeDx™) had Level I Evidence supporting: T1-T2 N0 M0 ER(+) HER2(-); RS <11 – Stage Group IA • Debate on including other profiles • Mammaprint– Based on MINDACT data published late August 2016 • Others Sparano JA et al. NEJM 2015;373:2005

32. Selection of Genomic Profiles for Use in Clinical Care The AJCC determined to include OncotypeDx in assigned Stage IA to T1-2 N0 ER+ HER2- RS<11; but recognizes that other profiles may be useful in clinical management. The AJCC Manual is NOT a practice guideline and the Expert Panel is NOT a guideline developer. Physicians are to use the best information available at the time to plan treatment, including the determination to use (one or several) genomic panels, and which genomic panel to select.

33. Cases of LABC defined by AJCC7 10,053 cases 74% changed stage Survival by AJCC7 Prognostic AJCC8 Wang M et al. The Breast 2018;37: 56-63 Survival for Locally Advanced Cancer:Anatomic vs. 8th Edition Prognostic - SEER Prognostic – AJCC 8 Anatomic – AJCC 7

34. Post Neoadjuvant Therapy Classification

35. AJCC 8th Edition Staging: 1-Page Guide POST NEOADJUVANT THERAPY STAGING CLASSIFICATION RULES • yc Clinical • Includes physical exam and imaging assessment • After neoadjuvant systemic/radiation therapy • yp Pathological • Includes all information from yc staging, • Surgeon’s operative findings and • Pathology report from resected specimen

36. Post Neoadjuvant Therapy Staging • Assigned after neoadjuvant therapy and surgical resection • ypT category • Largest focus of residual tumor • Treatment-related fibrosis near invasive tumor NOT used • Multiple foci of residual tumor, use (m) • ypN category • Largest focus of residual tumor in nodes • Treatment-related fibrosis near nodal tumor deposits NOT used • M category • If M1 prior to therapy, remains M1 following neoadjuvant therapy • Regardless of observed response to therapy • Assign degree of response to therapy

37. Stage Groups • Stage groups assigned using available tables in chapter • If no label on stage group table, use for • Clinical (c) • Pathological (p) or posttherapy (yp) • If stage group table is labeled, use as follows • Clinical group table used for c and yc • Pathological group table used for p and yp • IF posttherapy group table available • Use for yp and yc • Do NOT use p table

38. Stage Group Exceptions Breast • Clinical stage group table • Pathological stage group table • NO stage group assignment for posttherapy (yp) • Must record ypTypNcM Grade

39. Neoadjuvant Response • cT2 cN1 cM0 invasive ductal breast cancer. Neoadjuvant chemo 6 cycles followed by MRM w/axillary dissection. Pathology report is no residual tumor, nodes negative. • Neoadjuvant therapy destroyed all tumor, complete pathological response • ypT0 ypN0 cM0 stage 99 • Entered into new data item for posttherapy staging • Reminder - must meet criteria for neoadjuvant

40. Neoadjuvant No Response • 4.1cm breast tumor cT2 cN0. Neoadjuvant chemo 6 months. Post chemo imaging 6.5cm ycT3, no response. Surgical resection path 7.7cm, ypT3 ypN0. • Assign posttherapyyp staging ypT3 ypN0 cM0 • Some patients do not respond to neoadjuvant therapy • Analysis on response • If no data on cases not responding to neoadjuvant therapy • Data would only show cases that responded • Result in skewed analysis • Would not know effectiveness of neoadjuvant therapy & risk

41. Posttherapy Classification Assignment • Posttherapy classification assigned regardless of response • Always assign ypTypNcM • Does NOT depend on response to treatment • Even if pt responds completely, no evidence of tumor • Even if pt has partial response, tumor or nodes shrink • Even if pt did not respond, tumor/nodes stayed the same • Even if pt did not respond, tumor/nodes grew while on treatment • Not considered progression that stops staging • Not considered progression that makes surgery subsequent treatment

42. Colorectal Staging Tables – 8th Ed AJCC Cancer Staging Manual. 8th Ed. New York: Springer; 2017

43. Esophagus – Adenocarcinoma 8th Ed Staging Tables AJCC Cancer Staging Manual. 8th Ed. New York: Springer; 2017

44. Selecting Stage Group

45. Selecting Appropriate Stage Group Table:Anatomic Groups Not Used If Biomarker available • Anatomic Stage Groups • Appropriate for regions of world where biomarkers cannot be routinely obtained • Based solely on anatomic extent of cancer • Defined only by T, N, and M categories • Not appropriate where biomarkers are used for patient care

46. Selecting Appropriate Stage Group Table – Prognostic Staging for all Patients where Biomarker available • Clinical and Pathological Prognostic Stage Groups • Based on populations of breast cancer patients offered and mostly treated with endocrine and/or chemotherapy and/or anti-HER2 therapy • Includes T, N, M, tumor grade, HER2, ER, PR • Includes multi-gene panels • Can be based on clinical or pathological findings • Necessary for patient care • Must be used for reporting of all cancer patients in U.S.

47. Implementing Prognostic Stage in PracticeCannot memorize tables!!

48. 8th Edition API • License and deliver content professional organizations that need to update their products based on AJCC content • UICC: TNM + Stage groups for TNM manual • CAP: cancer protocols • NCCN: clinical practice guidelines • ASCO: CancerLinQ • American Cancer Society: patient education • Standard setters and registry software developers • Content being made available to vendors through API (currently being validated by registry vendors)

49. Incorporation into Daily Work Flow • Staging must be incorporated into EHR’s • Electronic data capture of key elements to present to managing physician to define final stage assignment • Integrate with oncology care pathways to define therapy • Include biologic / genomic data for individual cases • Incorporate into tools to assist patients with understanding and assisting with treatment decisions

50. AJCC licensing its Application Program Interface to EHR and pathway systems Direct entry by provider Records and documentation Decision support Example: Pathological staging screen from VIA Oncology Pathways Staging Calculators in Medical Records Systems